A large amount of clinical and basic research supports our current understanding that there are two major types of diabetes, termed IDDM and NIDDM. The disease process in classical IDDM patients is believed to be autoimmune in nature because of a strong association with certain HLA genes, the presence of humoral and cellular immune responses against islet antigens, and inflammatory infiltrate termed insulitis, the ability of T- cells to transfer IDDM, and the observation that immunotherapy alters the natural history of IDDM. In contrast, the disease process in NIDDM patients is not auto-immune in nature; a decreased sensitivity to insulin action is central to the disease process, and a poorly understood but non- inflammatory beta cell lesion occurs which diminished insulin secretory ability. The clinical distinction where NIDDM is very common, can have diabetes pathophysiologically similar to classical NIDDM, and some of the antibodies characteristic of IDDM can occur in older, obese individuals with phenotypic NIDDM. The main hypothesis to be tested in this project is that the pathophysiologic mechanism causing hyperglycemia in ICA and/or IAA, and/or GAD Ab, and/or ICA-512 positive, phenotypic NIDDM patients over the age of 40 (antibody positive NIDDM) is a combination of the Type I and Type II diabetes disease processes. The specific aims to be tested are: I. To compare the relative frequency of Type I diabetes susceptibility and protective genes (and gene loci) in Ab(+) NIDDM with relative frequency of the same genes in Ab(-) NIDDM, childhood IDDM, and normal controls. II. To compare the frequency of Type II diabetes susceptibility genes (and gene loci) in Ab(+) NIDDM with the frequency of these same genes in Ab(-) NIDDM, childhood IDDM, and normal controls. III. To compare ICA, GAD Ab, IAA, and ICA-512 frequency and levels, individually and in combination, in Ab(+) NIDDM with antibody frequency in childhood IDDM and to compare T-cell responses to islet antigens by cellular immunoblotting in Ab(+) NIDDM, Ab(-) childhood IDDM, and normal controls. IV. To compare T-cell Th2-type cytokine production with Th1-type cytokine production in Ab(=) NIDDM, childhood IDDM, Ab(-) NIDDM, and normal controls. V. To compare AIRmax, slope of glucose potentiation, and insulin sensitivity in Ab(+) NIDDM with these measures of beta cell function and insulin sensitivity in Ab(-) NIDDM, childhood IDDM, and normal controls. VI. To determine whether insulin treatment of recently diagnosed Ab(+) NIDDM results in greater preservation of residual beta cell function compared to treatment with glyburide or metformin.